Although cerebral venous hypertension is known as an important determinant factor for clinical manifestation and outcome in patients with dural arteriovenous malformation (AVM), the pathophysiology of that condition is not well understood. We have created a chronic rat model by cervical arteriovenous fistularization with jugular vein occlusion and examined effect of cerebral venous hypertension on cerebral blood flow regulation. This model may be suitable for investigating mechanisms of cerebrovascular alteration after venous hypertension. [Neurol Res 2003; 25: 694-696]

Keywords: Venous hypertension; dural AVM; cerebral blood flow; autoregulation; animal model

INTRODUCTION

Cerebral venous hypertension is considered an important mechanism that causes neurological symptoms and hemorrhage in patients with dural arteriovenous malformations (AVM)1-4. However, the pathophysiology of this particular condition is not well understood, partly because there is no pertinent animal model in the chronic period. We intended to make an animal model suitable for investigation of this chronic pathologic cerebral condition and to evaluate basic cerebral regulatory function.

MATERIALS AND METHODS

The animals in this study received humane care and treatment according to the Guide for the Care and Use of Laboratory Animals, published by the National Institute of Health (NIH publication 85-23, revised 1985).

Creation of cervical arteriovenous fistula and contralateral jugular vein ligation (Figure 1)

Male Sprague-Dawley rats (each weighing 270-390g), which were housed under diurnal lighting conditions and allowed free access to food and water, were anesthetized with 1.5% halothane and a mixture of oxygen and air. Surgery was performed under sterile conditions. The right common carotid artery (CCA) and the right posterior facial vein (PFV), which drains blood from the retroglenoid vein into the external jugular vein (EJV), were exposed by a midline neck incision. Rats were divided into two groups: fistula group and occlusion group. In the former group, a CCA-PFV fistula was constructed under an operating microscope by proximal CCA and distal PFV end-to-end anastomosis using 10-0 nylon. In the latter group, those were occluded by ligation. The wound was sutured (5-0 nylon) and the animals were monitored until full wake-up. After seven weeks all the animals were reanesthetized and underwent left PFV ligation.

General preparation for experiments

The rats were re-anesthetized 20 weeks after fistularization, initially with 1.5% halothane in 70% N^sub 2^O and 30% O2. Before each experiment the patency of the fistula was confirmed. The bilateral femoral arteries and vein were cannulated with a polyethylene catheter (PESO, Intramedic, Becton Dickinson, NJ, USA) for continuous arterial blood pressure, heart rate monitoring, blood withdrawal and drug administration. The rats were subjected to tracheostomy, placed in the stereotaxic frame and ventilated artificially. End-tidal CO2 was monitored by a CO2 analyzer (Respina IH3, San-ei, Tokyo, Japan). Urethane (750 mg kg^sup -1^) and [alpha]-chloralose (50 mgkg^sup -1^) were administered intraperitoneally and halothane was withdrawn gradually after completing surgery. An additional dose of urethane (150 mgkg^sup -1^) and [alpha]-chloralose (10 mgkg^sup -1^) were given as needed. Rats were immobilized with pancronium bromide (1 mg kg^sup -1^ i.p.). There was no blood pressure or pulse elevation in response to tail pinch during anesthesia. Arterial blood gas and pH were analyzed at baseline and after CO2 inhalation. Rectal temperature was maintained at approximately 37[degrees]C with a thermostatically controlled mat.

Pressure measurement

The superior sagittal sinus (SSS) at the vertex was exposed by a midline scalp incision and a small craniectomy using high-speed micro-drill (Fine Science Tools, Canada) and was punctured with a 24-gauge indwelling needle to monitor SSS pressure (SSSP). After physiological stabilization SSSP was recorded for at least 15 min.

Regional cerebral blood flow (rCBF) measurement

RCBF changes were continuously monitored with a laser-Doppler flowmeter (ALF21N, Advance Co., Tokyo, Japan) equipped with a 3 mW semiconductive laser with a wavelength of 780 nm over the right parietal cortex through a paper-thin layer of bone. To exclude pulsations of CBF and to obtain a mean value, we used an internai filter with a time constant of 3 sec. The probe and the drilled skull being measured were protected from direct light. Since the absolute LDF values from the monitor carry little meaning5,6, they were used only to calculate rCBF, expressed as percentages of baseline values.

Cerebral autoregulation

An initial rCBF recording was taken as 100% and subsequent flow changes were expressed relative to this value. After heparin (100 units i.v.) administration, arterial blood pressure was lowered by 10 mmHg every 5 min by withdrawing femoral arterial blood. Corresponding rCBF readings were averaged for each 10 mmHg stepwise reduction.

Statistical analysis

Data are presented as mean + or - standard deviation. Differences were compared by unpaired two-tailed Student's t-test (physiologic parameters, CO2 reactivity) or by two-way repeated measures ANOVA followed by Fisher's protected least-squares difference test (autoregulation). The software StatView 4.0 (Abacus Concepts, Inc., Berkeley, CA, USA) was used for statistical analysis, p-values of

RESULTS

Physiological variables are shown in Table 1. There were no within-group differences in mean arterial blood pressure and blood gas analysis.

Effects of fistula creation on SSSP and CO2 reactivity

SSSP rose significantly to 8.8 + or - 3.0 mmHg in the fistula group compared to the occlusion group (p=0.018). CO2 reactivity was 2.0% + or - 0.4%/mmHg and 2.7% + or - 1.4%/mmHg in the fistula group and occlusion group, respectively. There was no within-group difference (p=0.29).

Effects of cerebral venous hypertension on cerebral autoregulation (Figure 2)

During controlled exanguination CBF stayed relatively constant until

DISCUSSION

In the patient with dural AVM neurological symptoms are closely related to the pattern of venous drainage1,2, and angiographical cortical venous reflux and engorged pial vein is important as risk factors for aggressive manifestation5,4. Venous congestion or hypertension is considered as underlying pathology, however, it is not well understood partly because of the lack of ideal animal models. Bederson et al.7 reported that acute cerebral venous hypertension led to simultaneous significant flow velocity reduction in the ipsilateral middle cerebral artery by abrupt perfusion pressure decrease. In their rat model venous pressure rose to 35 mmHg immediately after jugular vein occlusion, which seemed not consistent with clinical situation. We modified this model into the chronic type and found constant SSSP increase by fistula creation with venous occlusion. In this model SSSP increased up to 9 mmHg after CCA-PFV fistularization. No rats showed neurological deficits, although we did not perform behavioral tests. Modest venous pressure increase in this model compared to Bederson's acute venous hypertension model may be explained by preserved anterior facial vein as an accessory collateral and by development of new channels during three months after fistularization. We changed the method of fistularization to CCA-EJV and found a higher SSSP increase - about 15 mmHg (preliminary results). For future investigation, this alteration may work to induce higher venous pressure in the chronic model. The cerebrovascular response to CO2 inhalation and acute hypotension was not altered in this model suggesting that mild venous hypertension does not alter these responses even in the chronic stage. Focal neurological deficits found in the patients are often reversible after dural AVM resection or occlusion. More study is necessary to elucidate mechanism of neuronal dysfunction induced by venous hypertension and its reversibility. Measurement of absolute cerebral blood flow, cerebral blood volume or neurological function or vasodilatory capacity in this type of chronic model may help understand the pathophysiology of venous hypertension. We should keep in mind that there may be differences between whole intracranial venous hypertension model and local venous hypertension found in clinical setting. Pathological examination is also mandatory to show effects of venous hypertension on neurons.

CONCLUSION

We created a chronic model of cerebral venous hypertension in rats by cervical arteriovenous fistularization with jugular vein occlusion and found intracranial venous sinus pressure significantly raised chronically whereas cerebral autoregulation and CO2 reactivity was preserved.

ACKNOWLEDGEMENTS

This work was supported in part by a Grant-in-Aid for Scientific Research (No. 11671387) and an Academic Frontier Project from the Japanese Ministry of Education, Science, Sports and Culture. The results of this study were presented at the 5th International Workshop on Cerebrovascular Surgery 1997, Fukuoka, Japan.

REFERENCES

1 Lasjaunias P, Chiu M, ter Brugge K, Tolia A, Hurth M, Bernstein M. Neurological manifestations of intracranial dural arteriovenous malformations. J Neurosurg 1986; 64: 724-730

2 Vinuela F, Fox AJ, Pelz DM, Drake CG. Unusual clinical manifestations of dural arteriovenous malformations. J Neurosurg 1986; 64: 554-558

3 Willinsky R. Venous congestion: An MR finding in dural arteriovenous malformations with cortical venous drainage. AJNK 1994; 15: 1501-1507

4 Willinsky R. Tortuous, elongated pial vein in intracranial dural arteriovenous fistulas: Correlation with presentation, location, and MR findings in 122 patients. AJNR 1999; 20: 1031-1036

5 Dirnagl U, Kaplan B, Jacewicz M, Pulsinelli W. Continuous measurement of cerebral cortical blood flow by laser-Doppler flowmetry in a rat stroke model. J Cereb Blood Flow Metab 1989; 9: 589-596

6 Iadecola C, Reis DJ. Continuous monitoring of cerebrocortical blood flow during stimulation of the cerebellar fastigial nucleus: A study by laser-Doppler flowmetry. J Cereb Blood Flow Metab 1990; 10: 608-617

7 Bederson JB, Wiestler OD, Brustle O, Roth P, Frick R, Yasargil MG. Intracranial venous hypertension and the effects of venous outflow obstruction in a rat model of arteriovenous fistula. Neurosurgery 1991; 29: 341-350

Masaru Yamada, Izumi Yuzawa, Kiyotaka Fujii and Yoshio Miyasaka*

Department of Neurosurgery, Kitasato University School of Medicine, Kanagawa * Yamato Municipal Hospital, Yamato, Japan

Correspondence and reprint requests to: Masaru Yamada, MD, Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. [yamadam@med.kitasato-u.ac.jp] Accepted for publication June 2003.

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